Wound healing is a complex process, and involves the regulation of numerous cellular functions including the interactions of fibroblasts/fibrocytes, osteoblasts, chondrocytes, endothelial cells, inflammatory cells, epithelial cells and smooth muscle cells, with the extracellular matrix. Normal healing results in scar formation in humans. However, it is well known that certain animals, and even the human fetus, are capable of regenerative healing of wounds which is indistinguishable from surrounding skin.
Although the intricate details of wound healing are still being discovered, the process follows along a typical time line having four phases:
Hemostasis Phase—This phase includes vasoconstriction lasting for the first 5-10 minutes after the injury.
Inflammation Phase—This phase includes vasodilation and a cellular response by inflammatory macrophages, neutrophils and fibroblasts. Neutrophils undergo cannbilaization to produce transforming growth factor beta-1 (TGF-β1), which stimulates production of type I collagen (the mature collagen present in nomal skin) and stimulates fibroblast to myofibroblasts mediated by hyaluronic acid and epidermal growth factor receptor (EGFR). Bacteria, foreign particles and damaged cells are removed from the wound. Vasodilation starts at about 10 minutes after the initial injury, and the cellular response typically starts 30 minutes after the initial injury. Keratinocytes detach from the basement membrane and migrate to cover the exposed wound and connective tissue, and the wound clot is replaced with epithelial cells and granulation tissue (type III collagen). Differentiating keratinocytes also produce TGF-β1. The cellular response may last 7 to 8 days.
Proliferation Phase—This phase includes re-epithelialization of the wound, fibroplasia, including collagen synthesis and wound contraction. During this phase skin cells multiply and spread, covering the wound. Re-epithelialization typically starts 24 hours after the injury. Fibroplasia typically starts in 3 to 4 days after the injury. Myofibroblasts (present in granulation tissue) express alpha-smooth muscle actin and are responsible for wound contraction, which typically starts 7 days after the injury.
Remodeling Phase—This phase includes scar/collagen remodeling. The newly formed collagen matrix becomes cross linked and organized starting about 3 weeks from wound initiation and lasting as long as 1 year.
Scar formation is a typical response for normal healing in humans. As compared with normal skin, a scar contains an overproduction of type III and type I collagens, and the mixture is disorganized. The scar itself is not very elastic and is of a different color than normal skin. The scar is also missing the layer of kertinocytes found on normal skin. Furthermore, depending on how deep was the original wound, the scar may be missing the normal underlying layers of muscle, fat, blood vessels, and many layers of the skin; these missing layers may result in the scar forming a depression compared to the level of the surrounding skin.
Some animals are capable of scar free healing. In axolotls, there is a substantial reduction in neutrophil infiltration and a relatively long delay in production of new extracellular matrix during scar free healing. Studies with athymic nude mice indicate that up-regulation in metalloproteinase-9 (MMP-9) throughout the remodeling phase may contribute to scar free healing. Matrix metalloproteinases (MMP's) are a family of zinc dependent enzymes capable of degradation of extracellular matrix and are vital to the remodeling of the matrix and migration of cells. During normal human wound healing, MMP-9 degrades the type IV collagen of the basement membrane allowing keratinocytes to detach from the basement membrane and migrate to cover the exposed wound and connective tissue.
Human oral healing of wounds results in little to no scar formation. Oral mucosal wounds show a robust early up-regulation of MMP-1, MMP-2 and MMP-9 at 3 days after the initial injury, as compared to skin wounds at 14 days after the initial injury. The human fetus, which also shows scar free healing, is surrounded by amniotic fluid which contains high molecular weight hyaluronic acid. High molecular weight hyaluronic acid is known to increase expression of MMP-2 and MMP-9. Although high molecular weight hyaluronic acid application at a wound site can reduce scarring, a scar is nevertheless still formed.
Resveratrol (trans-3,4′,5-trihydroxystilbene), a stilbenoid, is a grape polyphenol present in various plants, some food products, red wine and grapes. Resveratrol has anti-inflammatory, anti-carcinogenic and anti-oxidant properties, and has been extensively studied. Huge interest in resveratrol was created when it was discovered that it was able to active the SIRT1 gene, a gene implicated in the life span extension associate with calorie-restricted diets. However, resveratrol is poorly absorbed when consumed as a dietary supplement, and is subject to metabolic degradation, and beneficial effect have been difficult to observe in human clinical studies.